The long-term objectives are to discover and develop effective, non-toxic, targeted hormone therapies for patients with ER and PR negative breast cancer. Approximately 33% of breast cancers are ER and PR negative and patients with this type of cancer currently have no hormone therapy options. Their only option is chemotherapy. This research project focuses on patients with ER/ PR negative breast cancers that express the androgen receptor. The androgen receptor is present in about half of ER/PR negative breast cancers. This research proposal presents a novel therapeutic approach that uses agents which directly inhibit tumor growth and are ready to be tested in the clinical setting. This Phase I clinical trial will combine the androgen dehydroepiandrosterone, which is available as a dietary supplement, with the established anti-cancer drug letrozole to provide an unconventional pharmacological and biological intervention aimed at a novel cancer cell target. Responses to this treatment or in a subsequent phase II trial will be used as the rationale for conducting a national SWOG trial. The specific aims of the study will be: 1. To determine the maximum tolerable dose and dose limiting toxicity of the androgen dehydroepiandrosterone (DHEA) combined with letrozole. 2. To determine the pharmacokinetics of DHEA combined with letrozole. 3. To correlate DHEA and DHEAS levels clinically measured by enzyme immunoassays with levels measured by liquid chromatography/mass spectrometry 4. To determine whether virilizing side effects occur when DHEA is used as an androgen and, if so, at what dose and at what serum DHEA and DHEAS, testosterone and dihydrotestosterone levels they occur. 5. To determine if patients with ER-/PR-/AR+ breast cancer experience objective responses and/or clinical benefit from treatment with DHEA . Approximately 33% of breast cancers lack both ER and PR. They are considered hormone insensitive, as they do not respond to conventional hormone therapies. Patients with recurrent and metastatic ER -/ PR - tumors have only the option of receive chemotherapy and therefore less toxic treatment options for this group of patients are desperately needed. About 50% of ER-/PR- tumors express the androgen receptor (AR) and therefore may respond to and androgen based hormone therapy. If successful, this study will provide the first effective hormone treatment option for this type of breast cancer, which will be a major advancement in the treatment of ER-/PR- breast cancer. [unreadable] [unreadable] [unreadable]